Pain affects 1.5 billion people globally, including 116 million people in the USA and 164 million people in Europe and Israel combined. The 2009 global pain market was estimated to be over US $50 billion. Previous studies indicated that chronic pain occurs in about 20% of the general population, and the prevalence of neuropathic pain is 6.9%.
The clinical syndromes of the patients with neuropathic pain are accompanied by hyperalgesia, allodynia and spontaneous pain. In the same time, the use of opioids and other analgesics (including the non-steroidal anti-inflammatory drugs) will cause analgesic tolerance. In a review of 174 trials published, Finnerup et al. reported that there are no drug treatments available that can relieve all neuropathic pain conditions. (Finnerup N B et al., Pain. 150:573-81 (2010)) Moreover, the detailed mechanisms underlying neuropathic pain remain unclear. Therefore, the recent pain researches still focus on clarifying the possible mechanisms.
Clinical neuropathic pain syndromes are characterized by nociceptive behaviors such as evoked pain (hyperalgesia, mechanical allodynia and cold allodynia) and spontaneous pain (weight-bearing deficits) (Baron R., Handb Exp Pharmacol. 194:3-30. doi:10.1007/978-3-540-79090-7_1 (2009)), which can be measured by the nociceptive behavioral testing.
Spinal neuroinflammation may accelerate central sensitization and promote the development and maintenance of neuropathic pain, and spinal neuroinflammation is characterized by microglial and astrocytic activation and increased expression of the pro-inflammatory mediator tumor necrosis factor-α (hereinafter “TNF-α”). (Lin Y C et al., Behav Pharmacol., 22:739-50 (2011); Chen N F et al., J Pain., 14:1671-85 (2013))
Central sensitization within the dorsal horn of the spinal cord could contribute to the hypersensitive pain behaviors commonly observed with neuropathic pain. Activation of microglia and astrocytes could accelerate central sensitization. (Costigan M et al., Annu Rev Neurosci. 32:1-32 (2009); Myers R R et al., Drug Discov Today. 11:8-20 (2006); Streit W J et al., J Neuroinflammation. 2004; 1:14.) The nociceptive behaviors are accompanied by spinal microglial and astrocytic activation (Lin Y C et al., Behav Pharmacol. 22:739-50 (2011); Chen N F et al., Mar Drugs. 12:3792-817 (2014); Chen W F et al., Biomaterials. 53:1-11 (2015)), wherein the astrocyte plays an important role in nociceptive hypersensitization. (Fraser M M et al., Cancer Res. 64:7773-9 (2004); Ferraguti F et al., Exp Brain Res. 137:1-11 (2001))
Microglia and astrocytes play important roles for the maintenance as well as the development of neuropathic pain. (Hains B C and Waxman S G, J Neurosci. 26: 4308-17 (2006); Ji R R and Suter M R, Mol Pain. 3:33 (2007); Cao L et al., Eur J Immunol. 39:3562-9. (2009); Garrison C J et al., Brain Res. 565:1-7 (1991); Colburn R W et al., J Neuroimmunol. 79:163-75 (1997); Colburn R W et al., Exp Neurol. 157: 289-304 (1999); Coyle D E, Glia. 23:75-83 (1998); Stuesse S L et al., Exp Brain Res. 137:219-27 (2001))
Spinal microglia-astrocyte interactions could promote nociceptive responses. (Raghavendra V et al., J Neurosci. 20:467-73 (2004); Watkins L R et al., Pain. 71:225-35. (1997); Sung C S et al., Glia. 60:2004-17 (2012); Miyoshi K et al., J Neurosci. 28:12775-87 (2008); Davalos D et al., Nat Neurosci. 8:752-8 (2005); Lindia J A et al., J Pain. 6:434-8 (2005))
Upregulation of OX-42 (microglial marker) and GFAP (astrocytic marker) immunoreactivity in the spinal dorsal horn are known indicators of elevated nociceptive states. (Jean Y H et al., Br J Pharmacol. 158:713-25 (2009); Sweitzer S M et al., J Pharmacol Exp Ther. 297:1210-7 (2001); Ledeboer A et al., Pain. 115:71-83 (2005); Garrison C J et al., Brain Res. 565:1-7 (1991); Colburn R W et al., J Neuroimmunol. 79:163-75 (1997); Colburn R W et al., Exp Neurol. 157: 289-304 (1999); Coyle D E, Glia. 23:75-83 (1998); Stuesse S L et al., Neurosci Lett. 287: 121-4 (2000); Stuesse S L et al., Exp Brain Res. 137:219-27 (2001).)
Inhibition of microglial and astrocytic activation exerts analgesic effects. (Lin Y C et al., Behav Pharmacol. 22:739-50 (2011); Jean Y H et al., Br J Pharmacol. 158:713-25 (2009); Sweitzer S M et al., J Pharmacol Exp Ther 297:1210-7 (2001); Ledeboer A et al., Pain. 115:71-83 (2005))
TNF-α plays key roles in neuropathic pain, whereas, inhibition of spinal TNF-α inhibits neuropathic pain behavior (Leung L and Cahill C M, J Neuroinflammation. 7:27 (2010); Youn D H et al., J Neurosci Res. 86: 2867-75 (2008); Milligan E D et al., J Neurosci. 23:1026-40 (2003)).
Intra-articular adenovirus-mediated PTEN (hereinafter “Ad-PTEN”) has systemic anti-inflammatory effects. (Wang C R et al., Arthritis Rheum. 58:1650-6 (2008))
Inhibition of the spinal mammalian target of rapamycin (hereinafter “mTOR”) pathway of neuropathic rats can attenuate nociception and reduce neuroinflammation, and PTEN is considered an upstream inhibitory mediator of mTOR. Therefore, PTEN pathway is probably used for inhibiting downstream signaling of mTOR (Adkins J R et al., Am Surg. 70:384-7. discussion 387-388. (2004); Dello Russo C et al., Biochem Pharmacol. 78:1242-51 (2009); Lisi L et al, J Neuroinflammation. 8:1 (2011); Dello Russo et al. Glia. 61:301-11 (2013); Zhang W et al., Pharmacol Biochem Behav. 111:64-70 (2013); Geranton S M et al., J Neurosci. 29: 15017-27 (2009); Asante C O et al., J Pain. 11:1356-67 (2010)).
PTEN is a tumor suppressor gene. PTEN has been studied extensively through cancer research. Previous study has demonstrated that targeted disruption of Pten in Schwann cells causes focal hypermyelination in the PNS and is associated with progressive peripheral neuropathy in mice (Goebbels S et al., EMBO Mol Med. 4:486-99 (2012)). However, there is still a lack of evidence to show the role that PTEN plays for modulating pain.
Previous neuroscience studies have focused on the role of PTEN in axon regeneration, Alzheimer's disease, Parkinson's disease, ischemic brain injury, and spinal cord injury. There have been no past studies to explore the therapeutic effects of upregulation of PTEN on pain.